S-1 plus intravenous and intraperitoneal Paclitaxel for gastric cancer with peritoneal metastasis.

Peritoneal metastasis is the most frequent and life-threatening type of metastasis in patients with advanced gastric cancer. Despite recent advances in chemotherapeutic agents, any treatment, if administered only via the intravenous (IV) route, cannot satisfactorily control peritoneal metastasis in gastric cancer. Although intraperitoneal (IP) chemotherapy has been proposed as a treatment option, the clinical efficacy of IP chemotherapy for peritoneal lesions has not been examined in gastrointestinal cancer. One hundred patients with gastric cancer received combination chemotherapy of S-1 plus IV (50 mg/m(2)) and IP (20 mg/m(2)) paclitaxel (PTX) via a subcutaneously implanted peritoneal access port. S-1 was administered at 80 mg/m(2) per day for 14 consecutive days, followed by 7 days' rest. Radical gastrectomy was performed in a salvage setting when macroscopic curative resection was made feasible by the downstaging achieved by the combined chemotherapy. The median survival time (MST) of the patient sample was 23.6 months, with a 1-year survival of 80%. Combination chemotherapy of S-1 plus IV and IP PTX is well tolerated and very effective in patients with gastric cancer and peritoneal metastasis. Systemic chemotherapy combined with repeated IP administration of paclitaxel is a promising strategy for peritoneal carcinomatosis in gastrointestinal cancer.

[The updated treatment strategy for gastric cancer with peritoneal metastasis].

The standard of care for gastric cancer with peritoneal metastasis is chemotherapy. However, there is no chemotherapy regimen with a sufficient level of evidence, and thus S-1 plus cisplatin (CDDP), which is regarded as the standard regimen for advanced metastatic gastric cancer, is widely applied. Meanwhile the efficacy of intraperitoneal (IP) administration of taxanes has been verified, and the novel multidisciplinary treatment combining chemotherapy and surgery is now being tested. We developed a combination chemotherapy regimen of S-1, weekly intravenous and IP paclitaxel (PTX), and determined the recommended dose of IP PTX to be 20 mg/m2 in our phase I study. In our phase II study, the median survival time (MST) of 40 patients enrolled was 23.6 months, and peritoneal cytology turned negative for 86% of 28 patients. Moreover, we performed gastrectomy on 52 patients after disappearance or obvious shrinkage of peritoneal metastasis, and the MST was 34.9 months. The multidisciplinary treatment combining IP-containing chemotherapy and surgery is safe and effective for gastric cancer patients with peritoneal metastasis. We have just started a phase III trial (PHOENIX-GC trial) comparing our IP regimen versus S-1 plus CDDP.

Vagus nerve preservation selectively restores visceral fat volume in patients with early gastric cancer who underwent gastrectomy.

BACKGROUND: Body weight loss is a well-known complication after gastrectomy, and is mainly due to reduced fat volume. The effect of vagotomy on the postoperative fat volume was investigated in patients with early stage gastric cancer who underwent gastrectomy. METHODS: Subcutaneous fat area (SFA) and visceral fat area (VFA) were separately measured in a computed tomographic (CT) image at the level of the umbilicus using Fat Scan software. The changes in these two fat areas were determined by comparing CT images taken before and more than 6 mo after gastrectomy, and the ratio of postoperative to preoperative fat area was calculated in 77 patients. RESULTS: VFA was reduced significantly greater after total gastrectomy (TG) than distal gastrectomy (DG) (P = 0.0003). In 63 patients who underwent DG, the reduction in VFA, but not in SFA, was significantly less in vagus nerve-preserved than in vagus nerve-nonpreserved cases (59.0% ± 24.2% versus 74.9% ± 28.2%, P = 0.027). If compared in each case, VFA showed a significantly greater decrease than did SFA in vagus-nonpreserving, but not in vagus-preserving, gastrectomy (68.2% ± 37.0% versus 52.7% ± 25.2%, P < 0.0001; 76.3% ± 30.0% versus 74.9% ± 28.2%, P = 0.79). CONCLUSIONS: The vagus nerve has a function to locally regulate the amount of intra-abdominal fat tissue, and selective vagotomy in gastrectomy results in a preferential reduction of visceral fat in gastrectomy. Surgical denervation of vagus may be reconsidered as a reasonable treatment for excessive obesity.

Clinical significance of CA125 and CA72-4 in gastric cancer with peritoneal dissemination.

BACKGROUND: Serum tumor markers have been shown to correlate with the clinical status of patients with advanced gastric cancer. However, the clinical significance of each tumor marker in patients with peritoneal dissemination has not been fully verified. METHODS: Four serum markers, carcinoembryonic antigen (CEA), carbohydrate antigen (CA) 19-9, CA125, and CA72-4, were periodically measured in 102 patients with peritoneal dissemination who received combination intravenous and intraperitoneal chemotherapy. The initial values at diagnosis and after treatment were analyzed in association with clinicopathological factors, response to chemotherapy, and overall survival. RESULTS: The sensitivities of CEA, CA19-9, CA125, and CA72-4 for peritoneal metastasis at the initial diagnosis were 19, 36, 46, and 45%, respectively. The CA125 level was significantly correlated with the degree of peritoneal dissemination and the existence of malignant ascites. Patients with ovarian metastasis showed significantly higher levels of CA72-4. The median survival time of patients with an elevated CA125 level was significantly shorter than that of patients with a normal CA125 level (36.7 vs. 16.6 months, p < 0.001). Multivariate analysis showed that the degree of peritoneal metastasis and an elevated CA125 level were independent prognostic factors. Normalization of the CA125 level after 3 courses of chemotherapy was correlated with reduced ascites and improved survival. CONCLUSIONS: Serum CA125 and CA72-4 are clinically useful markers in diagnosis, evaluating the efficacy of chemotherapy, and predicting the prognosis of patients with peritoneal dissemination. From an academic point of view, periodic measurements of these markers are warranted in gastric cancer patients with possible peritoneal dissemination.

Frequent development of leptomeningeal carcinomatosis in patients with peritoneal dissemination of gastric cancer.

We detected 7 cases of leptomeningeal carcinomatosis in 126 patients with peritoneal dissemination of gastric cancer who received combined systemic and intraperitoneal chemotherapy. Leptomeningeal carcinomatosis was diagnosed 79-1540 days after the diagnosis of the primary gastric cancer. Patients presenting with various neurological symptoms were diagnosed by cerebrospinal fluid (CSF) cytology and radiological imaging. Irradiation to the whole brain and spine was performed in 4 patients, and provided palliation and increased survival for 1 patient. Intrathecal chemotherapy and drainage of CSF was performed in 1 patient each, but produced no significant clinical benefit in either of them. Survival after the diagnosis of leptomeningeal carcinomatosis was between 3 and 155 days. As patients with peritoneal dissemination of gastric cancer are living longer because of improved chemotherapy, clinicians must recognize the possibility of leptomeningeal carcinomatosis when patients complain of neurological symptoms.

Loss of sympathetic nerve fibers around intratumoral arterioles reflects malignant potential of gastric cancer.

BACKGROUND: The role and clinical significance of the alteration of sympathetic nerve fibers (SNF) was assessed in gastric cancer. Loss of nerve fibers in malignant tumors has previously been described; however, how dysfunction of the nervous system is involved in cancer progression has not been clarified in clinical studies. MATERIALS AND METHODS: The distribution of SNF was examined in 82 surgically resected gastric cancer specimens with immunohistochemical staining of tyrosine hydroxylase (TH), and the association with clinicopathological findings as well as the clinical outcome of the patients was retrospectively evaluated. RESULTS: Arterioles in the normal gastric wall were totally covered with SNF, while the immunoreactivity to TH was markedly reduced around arterioles in cancer tissue. The degree of loss of SNF was significantly correlated with the depth of invasion (P < .0001) and lymph node metastasis (P < .0001) as well as microvessel density (MVD) (P = .0043). Moreover, patients who had tumors with marked loss of SNF showed a markedly worse clinical outcome, with an independent association by multivariate analysis. CONCLUSIONS: Loss of periarteriolar SNF is associated with aggressive phenotype of gastric cancer possibly through enhanced angiogenesis and thus could be a useful marker to predict the clinical outcome.

Spatial distribution of intraperitoneally administrated paclitaxel nanoparticles solubilized with poly (2-methacryloxyethyl phosphorylcholine-co n-butyl methacrylate) in peritoneal metastatic nodules.

Intraperitoneal (i.p.) administration of paclitaxel nanoparticles (PTX-30W) prepared by solubulization with the amphiphilic copolymer of 2-methacryloxyethyl phosphorylcholine and n-butyl methacrylate can efficiently suppress the growth of peritoneal metastasis. In this study, we characterized the drug distribution of i.p. injected PTX-30W in peritoneal tumor and liver in a mouse model using MKN45, human gastric cancer cells. Oregon green-conjugated PTX-30W showed perivascular accumulation in MKN45 tumor in the peritoneum at 24 h after intravenous (i.v.) injection; however, the amount of PTX in tumor was markedly less than that in liver. In contrast, a larger amount of PTX accumulated in the peripheral area of disseminated nodules at 1 h after i.p. injection and the area gradually enlarged. The depth of PTX infiltration reached 1 mm from the tumor surface at 48 h after i.p. injection, and the fluorescence intensity was markedly greater than that in liver. Interestingly, i.p. injected PTX preferentially accumulated in relatively hypovascular areas, and many tumor cells in the vicinity of PTX accumulation showed apoptosis. This unique accumulation pattern and lesser washout in hypovascular areas are thought to be attributable to the superior penetrating activity of PTX-30W, and thus, PTX-30W is considered to be highly suitable for i.p. chemotherapy for peritoneal dissemination.

Analysis of pO(2) in Malignant Ascites of Patients with Peritoneal Dissemination of Gastric Cancer.

OBJECTIVE: Oxygen is one of the most important environmental factors for tumor development. In this study, we examined pO(2) in malignant ascites in patients with peritoneal carcinomatosis. METHODS: In 21 patients with peritoneal dissemination of gastric cancer, ascitic fluid was collected and its pH, pCO(2) and pO(2) were determined using a blood gas analyzer. RESULTS: In 21 patients, pH of malignant ascites was significantly lower than that of arterial blood (7.39 ± 0.07, 7.44 ± 0.02, p < 0.05). Accordingly, pCO(2) tended to be higher in ascites than in arterial blood. Unexpectedly, pO(2) in malignant ascites showed relatively high values (90.4 ± 27.72 mm Hg), which were mostly the same as those of arterial blood (97.09 ± 10.33 mm Hg, p = 0.858). Even in 19 patients whose samples were collected at bedside in room air, pO(2) of malignant ascites was 85.94 ± 23.94 mm Hg, which was patently higher than that in venous blood or in solid tumor tissues. CONCLUSION: Since the oxygen level critically affects the sensitivity of tumor cells to chemotherapeutic agents through metabolic transformation, the oxygenic condition in the peritoneal cavity may be beneficial for the progression of peritoneal metastasis, and also clinically important in considering the efficacy of chemotherapy.

[Three cases of metastatic breast cancer effectively treated with S-1 therapy].

We experienced 3 cases of recurrent breast cancer treated with S-1 therapy, delaying tumor progression and improving their quality of life (QOL). All the patients had been previously treated with both anthracyclines and/or taxanes prior to S-1 chemotherapy. All patients almost completed the full dose through the whole course of treatment, and the drug showed good tolerability. Long-term(more than 12 weeks)therapeutic efficacy and the patients' QOL have been maintained for all patients. No major side effects were seen. It is thought that less toxicity enabled patient 3 to undergo long-term therapy. It is especially important that one patient had therapeutic efficacy and QOL improvement from treatment with S-1 and aromatase inhibitor for over 3 years, after being treated with anthracyclines, taxanes and vinorelbine. We conclude that S-1 is effective and well tolerated in patients with metastatic breast cancer, and will accommodate a long-time progression with respect to efficacy and maintaining the patients' QOL. Further evaluation of S-1 is necessary to elucidate its clinical role in breast cancer treatment.

Weekly intravenous and intraperitoneal paclitaxel combined with S-1 for malignant ascites due to advanced gastric cancer.

Malignant ascites caused by gastric cancer are chemotherapy resistant and carry a poor prognosis. The efficacy of a regimen including intraperitoneal paclitaxel (PTX) was evaluated in 33 gastric cancer patients with ascetic fluid in the peritoneal cavity diagnosed with computed tomography (CT) scanning. Synchronous administration of intravenous (50 mg/m(2)) and intraperitoneal (20 mg/m(2)) PTX was performed via a subcutaneously placed intraperitoneal catheter on days 1 and 8, and S-1 was administered twice daily at 80 mg/m(2)/day for 14 consecutive days from day 1 to day 14, followed by 7 days of rest. The ascitic fluid volume was calculated with NIH Image J software using continuous CT images. After 2-4 treatment cycles, 23 (70%) patients showed reductions in their ascitic volumes of >50%. Ascites disappeared completely in 8 patients and were markedly reduced (to <3% of the original volume) in 4 of the 9 patients (44%) who initially had massive (>2,500 ml) ascites. Median overall survival was significantly better in patients with ascitic reduction. Weekly intravenous and intraperitoneal PTX combined with S-1 was highly effective in gastric cancer with malignant ascites. The change in ascitic fluid volumes determined by CT image measurements is a useful predictor of outcome in these patients.

Phase I study of biweekly intravenous paclitaxel plus intraperitoneal cisplatin and paclitaxel for gastric cancer with peritoneal metastasis.

OBJECTIVES: A phase I study of biweekly intravenous (IV) paclitaxel (PTX) plus intraperitoneal (IP) cisplatin (CDDP) and PTX was performed to determine the maximum tolerated dose (MTD) and recommended dose (RD) in gastric cancer patients. METHODS: Nine gastric cancer patients with peritoneal metastasis were enrolled. PTX was administered intravenously at a dose of 100 mg/m(2) and intraperitoneally with an initial dose of 20 mg/m(2) (level 1), stepped up to 30 or 40 mg/m(2) depending on observed toxicity. CDDP was administered intraperitoneally at a dose of 30 mg/m(2) over 24 h. PTX and CDDP were administered on days 1 and 15 in 4-week cycles. RESULTS: The MTD was determined to be dose level 1, as 2 of 3 patients experienced dose-limiting toxicities (DLTs), grade 4 leukopenia and grade 3 vomiting. Therefore, the doses of IV PTX, IP CDDP and IP PTX were reduced to 80, 25 and 20 mg/m(2), respectively (level 0). Consequently, the RD was determined to be dose level 0, as only 1 of 6 patients experienced DLT, grade 3 nausea. CONCLUSIONS: Combination chemotherapy of IV PTX plus IP CDDP and PTX was shown to be a safe regimen that should be further explored in clinical trials.

Solitary splenic metastasis from early gastric cancer: report of a case.

Solitary metastasis of a malignancy to the spleen is rare. We herein describe a case of splenic metastasis from early gastric cancer. A 76-year-old man underwent an endoscopic mucosal resection (EMR) for early gastric carcinoma in the cardia. Pathologically, the tumor showed invasion into the submucosal layer, and the stump of the surgical specimen appeared to be positive for malignant cells. He thus underwent a proximal gastrectomy with nodal dissection. One year later, serum carcinoembryonic antigen was elevated, and a splenic mass was detected by computed tomography and ultrasonography. Because the tumor increased in size very gradually and no metastatic lesions were detected at the other sites, we performed a splenectomy. The lesion was pathologically diagnosed as metastasis from the previous gastric carcinoma, and the patient remains healthy to date without recurrence, more than 2 years after the splenectomy. When solitary metastasis to the spleen is suspected during the postoperative follow-up of a patient with gastric cancer, a splenectomy is a potentially effective treatment.

Intraperitoneal administration of paclitaxel solubilized with poly(2-methacryloxyethyl phosphorylcholine-co n-butyl methacrylate) for peritoneal dissemination of gastric cancer.

Intraperitoneal (i.p.) administration of paclitaxel (PTX) is a hopeful therapeutic strategy for peritoneal malignancy. Intravenously (i.v.) injected nanoparticle anticancer drugs are known to be retained in the blood stream for a long time and favorably extravasated from vessels into the interstitium of tumor tissue. In this study, we evaluated the effect of i.p. injection of PTX (PTX-30W), which was prepared by solubulization with water-soluble amphiphilic polymer composed of PMB-30W, a co-polymer of 2-methacryloxyethyl phosphorylcholine and n-butyl methacrylate, for peritoneal dissemination of gastric cancer. In a peritoneal metastasis model with transfer of MKN45P in nude mice, the effect of i.p. administration of PTX-30W was compared with conventional PTX dissolved in Cremophor EL (PTX-Cre). The drug accumulation in peritoneal nodules was evaluated with intratumor PTX concentration and fluorescence microscopic observation. PTX-30W reduced the number of metastatic nodules and tumor volume significantly more than did conventional PTX dissolved in Cremophor EL (PTX-Cre), and prolonged the survival time (P < 0.05). PTX concentration in disseminated tumors measured by HPLC was higher in the PTX-30W than in the PTX-Cre group up to 24 h after i.p. injection. Oregon green-conjugated PTX-30W, i.p. administered, preferentially accumulated in relatively hypovascular areas in the peripheral part of disseminated nodules, which was significantly greater than the accumulation of PTX-Cre. I.p. administration of PTX-30W may be a promising strategy for peritoneal dissemination, due to its superior characteristics to accumulate in peritoneal lesions.

Phase I pharmacokinetic study of weekly intravenous and intraperitoneal paclitaxel combined with S-1 for advanced gastric cancer.

OBJECTIVES: A dose-escalation study of weekly intraperitoneal paclitaxel (PTX) combined with S-1 and intravenous PTX was performed to determine the maximum-tolerated dose (MTD) and recommended dose (RD) in gastric cancer patients. PATIENTS AND METHODS: Nine gastric cancer patients with peritoneal dissemination and/or cancer cells on peritoneal cytology were enrolled. PTX was administered intravenously on days 1 and 8 at a fixed dose of 50 mg/m(2), and intraperitoneally with an initial dose of 20 mg/m(2), stepped up to 30 or 40 mg/m(2). S-1 was administered at a fixed dose of 80 mg/m(2)/day for 14 consecutive days, followed by 7 days of rest. A pharmacokinetic study of PTX was also performed. RESULTS: The MTD was determined to be 30 mg/m(2), as 2 of 3 patients developed dose-limiting toxicities, grade 3 febrile neutropenia and diarrhea. Therefore, the RD was determined to be 20 mg/m(2). The intraperitoneal and serum PTX concentration remained effective for over 72 and 48 h, respectively. CONCLUSIONS: Combined chemotherapy of S-1 plus weekly intravenous and intraperitoneal PTX was shown to be a safe regimen that should be further explored in clinical trials.

Different tissue distribution of paclitaxel with intravenous and intraperitoneal administration.

PURPOSE: Paclitaxel is considered to be suitable for disseminated cancer in the peritoneal cavity because of its high molecular weight and lipophilic characteristics. However, the difference in pharmacokinetics of paclitaxel after intraperitoneal (i.p.) and intravenous (i.v.) administration is not fully defined. Here, we investigated the tissue concentration of paclitaxel in various organs at various time points after i.p. or i.v. administration. METHODS: Paclitaxel (5 mg/kg) was administrated in an ear vein or in the abdominal cavity of rabbits. At 0.5, 6, 24, and 48 h after administration, the rabbits were sacrificed, and organs as well as peripheral blood were harvested. The serum and tissue concentrations of paclitaxel were measured by HPLC procedure. RESULT: The concentration of paclitaxel was high in the i.v. group at 0.5 h, whereas it was significantly higher in the i.p. group at 6 and 24 h. The AUC (area under the curve) was markedly higher in the omentum, mesenteric lymph nodes as well as ovary and stomach in the i.p. group. CONCLUSION: Compared with i.v. administration, paclitaxel concentration was maintained at a high level in the whole body by i.p. administration. Repeated i.p. paclitaxel can produce more marked clinical effects than i.v. administration for metastatic lymph nodes and primary lesions as well as peritoneal dissemination.

Intra-peritoneal administration of paclitaxel with non-animal stabilized hyaluronic acid as a vehicle--a new strategy against peritoneal dissemination of gastric cancer.

BACKGROUND AND AIM: Intra-peritoneal administration (i.p.) of Taxanes has recently been reported to be effective for the treatment of peritoneal dissemination, presumably because extremely high concentration of the drug is achievable onto the disseminated nodules as compared to intra-venous administration. Here, we aimed to investigate the ability of non-animal stabilized hyaluronic acid (NASHA) to retain the anti-cancer drugs in the peritoneal cavity, and, consequently, improve the efficacy of i.p. administration of paclitaxel. METHODS: Mice were inoculated i.p. with MKN45P gastric cancer cells. The mice received i.p. administrations of paclitaxel, without or with NASHA, once a week for 3 consecutive weeks, and the intra-peritoneal nodules were counted after 4 weeks. The ability of NASHA to retain the i.p. administered liquid and paclitaxel in abdominal cavity was also investigated. Finally, the concentration of paclitaxel in metastatic nodule was measured with HPLC. RESULTS: In the group receiving paclitaxel with NASHA, the number of disseminated nodules were significantly smaller than in those receiving paclitaxel without NASHA. The fluid volumes and concentration of paclitaxel recovered from the abdominal cavity as well as the concentrations of paclitaxel in metastatic nodule were significantly increased by the addition of NASHA. CONCLUSION: Our results indicate that NASHA improves the exposure time of i.p. administrated paclitaxel to disseminated nodules by retaining the drug in the abdominal cavity. Since the material is used in cosmetic surgery with few adverse effects, NASHA can be clinically used as the vehicle for the i.p. administration of anti-cancer agents for advanced gastric cancer with peritoneal dissemination.

Early gastric cancer shows different associations with adipose tissue volume depending on histological type.

BACKGROUND: Visceral obesity is known to be a risk factor for diabetes and cardiovascular disease. Cancer of the gastric cardia has been shown to have a close association with obesity in Western countries. In order to examine the possible relationship between fat volume and the development of gastric cancer (GC), we quantified visceral and subcutaneous fat areas of computed tomography (CT) images of patients with early GC. METHODS: A total of 210 patients who underwent endoscopic resection or surgical gastrectomy and whose disease was pathologically diagnosed as early GC were investigated for total fat area (TFA), visceral fat area (VFA), and subcutaneous fat area (SFA) with Fat Scan software, using a CT slice at the umbilical level, and the relationships of these findings with clinical and pathological data were analyzed. The same analysis was performed in 147 patients with early colorectal cancer (CRC). RESULTS: TFA, VFA, and SFA values in GC patients were not significantly different from the values in CRC patients. These values did not differ with the location of the GC. However, patients with undifferentiated-type GC had significantly smaller VFAs and SFAs than those with differentiated-type GC. Among the patients with undifferentiated GC, TFA and SFA values in the patients with submucosal cancer were significantly smaller than those in the patients with mucosal cancer. CONCLUSION: GC has different associations with adipose tissue volume according to its histological type. As compared with differentiated GC, lower adipose tissue volume may be a preferential environment for the development and progression of undifferentiated GC.

Metastatic esophageal tumor from cecal carcinoma.

A 55-year-old man developed progressive dysphagia 14 months after palliative colectomy and subsequent systemic chemotherapy for advanced cecal cancer with carcinomatosis peritonei. Radiologic and endoscopic examinations suggested a submucosal tumor in the lower esophagus causing a severe luminal stricture. A self-expanding metal stent was placed for palliation. The prosthesis was effective for several months, but ingrowth of the tumor caused re-stricture of the esophagus. Since his general condition was quite good without any evidence of recurrence of the cecal cancer, we performed bypass surgery for palliation. The pathological appearance of the tumor was compatible with the metastasis of cecal cancer. Our case suggests that a surgical approach can be considered as a therapeutic method for metastatic esophageal tumor, even in patients with advanced cancer, as long as the primary tumor is satisfactorily controlled.

Solitary nodal recurrence in the dorsal area of the thoracic aorta after a curative resection of esophageal cancer: report of two cases.

Although locoregional recurrence is often observed in the cervicothoracic area even after an esophagectomy with three-field lymph node dissection (3FL), recurrence in the mediastinal lymph nodes is relatively rare. We experienced two cases of solitary recurrence in a posterior mediastinal node (No 112-ao) after a curative resection for thoracic esophageal cancer. The lymph node recurrence was located in the connective tissue adjacent to the left posterior wall of the thoracic aorta, and thus could not have been removed by the conventional approach of an esophagectomy through a right thoracotomy. These two patients underwent surgical removal of the tumor through left thoracotomy, and survived for 5 years and 1 year without recurrence, respectively. Because the rate of metastasis in this area appears to be low, it is not always necessary to perform complete nodal dissection of the left side of the descending aorta at the initial surgery in cases of thoracic esophageal cancer. However, our experience suggests the importance of periodic computed tomography scans to check for any nodal recurrence in this area, since a surgical resection may be effective when the recurrence is detected as a solitary metastasis.